DNA Damage Repair in Glioblastoma: A Novel Approach to Combat Drug Resistance

Abstract

Due to the lack of effective therapeutic approach, glioblastoma (GBM) remains one of the most malignant brain tumour. By in vitro investigations on primary GBM stem cells, we highlighted one of the underlying mechanisms of drug resistance to alkylating agents, the DNA damage responses. Here, flow cytometric analysis and viability and repopulation assays were used to assess the long-term cytotoxic effect induced by the administration of a fourth-generation platinum prodrug, the (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato) platinum(IV) named Pt(IV)Ac-POA, in comparison to the most widely used Cisplatin. The immunofluorescence studies revealed changing pathways involved in the DNA damage response mechanisms in response to the two chemotherapies, suggesting in particular the role of Poly (ADP-Ribose) polymerases in the onset of resistance to Cisplatin-induced cytotoxicity. Thus, this research provides a proof of concept for how the use of a prodrug which allows the co-administration of Cisplatin and an Histone DeACetylase inhibitors, could suppress DNA repair mechanisms, suggesting a novel effective approach in GBM treatment.

Keywords

chemotherapy / DNA damage response / drug resistance / glioblastoma

References

[1] D. N. Louis, A. Perry, P. Wesseling, et al., “The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary,” Neuro-Oncology 23 (2021): 1231-1251, https://doi.org/10.1093/neuonc/noab106.

[2] А. Kosianova, O. Pak, and I. Bryukhovetskiy, “Regulation of Cancer Stem Cells and Immunotherapy of Glioblastoma (Review),” Biomedical Reports 20 (2023): 24, https://doi.org/10.3892/br.2023.1712.

[3] J. C. Madukwe, “Overcoming Drug Resistance in Cancer,” Cell 186 (2023): 1515-1516, https://doi.org/10.1016/j.cell.2023.03.019.

[4] G. Finocchiaro and S. Pellegatta, “Immunotherapy With Dendritic Cells Loaded With Glioblastoma Stem Cells: From Preclinical to Clinical Studies,” Cancer Immunology, Immunotherapy 65 (2016): 101-109, https://doi.org/10.1007/s00262-015-1754-9.

[5] Y. Li, Z. Wang, J. A. Ajani, and S. Song, “Drug Resistance and Cancer Stem Cells,” Cell Communication and Signaling: CCS 19 (2021): 1-11, https://doi.org/10.1186/s12964-020-00627-5.

[6] E. Gabano, M. Ravera, I. Zanellato, et al., “An Unsymmetric Cisplatin-Based Pt(IV) DerIVatIVe Containing 2-(2-Propynyl)Octanoate: A Very Efficient Multi-Action Antitumor Prodrug Candidate,” Dalton Transactions 46 (2017): 14174-14185, https://doi.org/10.1039/c7dt02928d.

[7] T. Groh, J. Hrabeta, M. A. Khalil, H. Doktorova, T. Eckschlager, and M. Stiborova, “The Synergistic Effects of DNA-Damaging Drugs Cisplatin and Etoposide With a Histone Deacetylase Inhibitor Valproate in High-Risk Neuroblastoma Cells,” International Journal of Oncology 47 (2015): 343-352, https://doi.org/10.3892/ijo.2015.2996.

[8] Y. Sun, X. Bao, Y. Ren, et al., “Targeting HDAC/OAZ1 Axis With a Novel Inhibitor Effectively Reverses Cisplatin Resistance in Non-Small Cell Lung Cancer,” Cell Death & Disease 10 (2019): 400, https://doi.org/10.1038/s41419-019-1597-y.

[9] F. B. Kraft, L. Biermann, L. Schäker-Hübner, et al., “Hydrazide-Based Class I Selective HDAC Inhibitors Completely Reverse Chemoresistance Synergistically in Platinum-Resistant Solid Cancer Cells,” Journal of Medicinal Chemistry 67 (2024): 17796-17819, https://doi.org/10.1021/acs.jmedchem.4c01817.

[10] A. Granit, K. Mishra, D. Barasch, T. Peretz-Yablonsky, S. Eyal, and O. Kakhlon, “Metabolomic Profiling of Triple Negative Breast Cancer Cells Suggests That Valproic Acid Can Enhance the Anticancer Effect of Cisplatin,” Frontiers in Cell and Development Biology 10 (2022): 1014798, https://doi.org/10.3389/fcell.2022.1014798.

[11] A. Gupta and P. K. Sasmal, “Multi-Functional Biotinylated Platinum (iv)-SAHA Conjugate for Tumor-Targeted Chemotherapy,” Dalton Transactions 53 (2024): 17829-17840, https://doi.org/10.1039/D4DT01571A.

[12] L. Y. Li, Y. D. Guan, X. S. Chen, J. M. Yang, and Y. Cheng, “DNA Repair Pathways in Cancer Therapy and Resistance,” Frontiers in Pharmacology 11 (2021): 1-13, https://doi.org/10.3389/fphar.2020.629266.

[13] Z. Sharifi, B. Abdulkarim, B. Meehan, et al., “Mechanisms and Antitumor Activity of a Binary EGFR/DNA-Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide,” Clinical Cancer Research 25 (2019): 7594-7608, https://doi.org/10.1158/1078-0432.CCR-19-0955.

[14] D. Hanisch, A. Krumm, T. Diehl, et al., “Class I HDAC Overexpression Promotes Temozolomide Resistance in Glioma Cells by Regulating RAD18 Expression,” Cell Death & Disease 13 (2022): 293, https://doi.org/10.1038/s41419-022-04751-7.

[15] A. Ferri, V. Stagni, and D. Barilà, “Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma,” International Journal of Molecular Sciences 21 (2020): 1-19, https://doi.org/10.3390/ijms21144910.

[16] D. Tiek and S. Y. Cheng, “DNA Damage and Metabolic Mechanisms of Cancer Drug Resistance,” Cancer Drug Resistance 5 (2022): 368-379, https://doi.org/10.20517/cdr.2021.148.

[17] L. M. Røst, S. B. Ræder, C. Olaisen, et al., “PCNA Regulates Primary Metabolism by Scaffolding Metabolic Enzymes,” Oncogene 42 (2023): 613-624, https://doi.org/10.1038/s41388-022-02579-1.

[18] E. Rodler, P. Sharma, W. E. Barlow, et al., “Cisplatin With Veliparib or Placebo in Metastatic Triple-Negative Breast Cancer and BRCA Mutation-Associated Breast Cancer (S1416): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial,” Lancet Oncology 24 (2023): 162-174, https://doi.org/10.1016/S1470-2045(22)00739-2.

[19] C. R. R. Rocha, M. M. Silva, A. Quinet, J. B. Cabral-Neto, and C. F. M. Menck, “DNA Repair Pathways and Cisplatin Resistance: An Intimate Relationship,” Clinics 73 (2018): 1-10, https://doi.org/10.6061/clinics/2018/e478s.

[20] J. Michels, I. Vitale, L. Senovilla, et al., “Synergistic Interaction Between Cisplatin and PARP Inhibitors in Non-Small Cell Lung Cancer,” Cell Cycle 12 (2013): 877-883, https://doi.org/10.4161/cc.24034.

[21] E. Lu, I. Gareev, C. Yuan, et al., “The Mechanisms of Current Platinum Anticancer Drug Resistance in the Glioma,” Current Pharmaceutical Design 28 (2022): 1863-1869, https://doi.org/10.2174/1381612828666220607105746.

[22] J. Jeon, S. Lee, H. Kim, et al., “Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas,” International Journal of Molecular Sciences 22, no. 10 (2021): 5111, https://doi.org/10.3390/ijms22105111.

[23] A. Basu and S. Krishnamurthy, “Cellular Responses to Cisplatin-Induced DNA Damage,” Journal of Nucleic Acids 2010 (2010): 201367, https://doi.org/10.4061/2010/201367.

[24] R. Huang and P. K. Zhou, “DNA Damage Repair: Historical Perspectives, Mechanistic Pathways and Clinical Translation for Targeted Cancer Therapy,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 254, https://doi.org/10.1038/s41392-021-00648-7.

[25] A. R. Z. Almotairy, V. Gandin, L. Morrison, C. Marzano, D. Montagner, and A. Erxleben, “Antitumor Platinum(IV) Derivatives of Carboplatin and the Histone Deacetylase Inhibitor 4-Phenylbutyric Acid,” Journal of Inorganic Biochemistry 177 (2017): 1-7, https://doi.org/10.1016/j.jinorgbio.2017.09.009.

[26] A. R. Z. Almotairy, D. Montagner, L. Morrison, M. Devereux, O. Howe, and A. Erxleben, “Pt(IV) pro-Drugs With an Axial HDAC Inhibitor Demonstrate Multimodal Mechanisms Involving DNA Damage and Apoptosis Independent of Cisplatin Resistance in A2780/A2780cis Cells,” Journal of Inorganic Biochemistry 210 (2020): 111125, https://doi.org/10.1016/j.jinorgbio.2020.111125.

[27] D. Tolan, A. R. Z. Almotairy, O. Howe, M. Devereux, D. Montagner, and A. Erxleben, “Cytotoxicity and ROS Production of Novel Pt(IV) Oxaliplatin Derivatives With Indole Propionic Acid,” Inorganica Chimica Acta 492 (2019): 262-267, https://doi.org/10.1016/j.ica.2019.04.038.

[28] M. Drzewiecka, D. Jaśniak, G. Barszczewska-Pietraszek, et al., “Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells,” Journal of Personalized Medicine 13 (2023): 1315, https://doi.org/10.3390/jpm13091315.

[29] A. L. Ferreira, A. Menezes, V. Sandim, et al., “Histone Deacetylase Inhibition Disrupts the Molecular Signature of the Glioblastoma Secretome Related to Extracellular Vesicle-Associated Proteins and Targets RAB7a and RAB14 In Vitro,” Biochemical and Biophysical Research Communications 736 (2024): 150847, https://doi.org/10.1016/j.bbrc.2024.150847.

[30] A. Gopinathan, R. Sankhe, E. Rathi, et al., “An In Silico Drug Repurposing Approach to Identify HDAC1 Inhibitors Against Glioblastoma,” Journal of Biomolecular Structure & Dynamics (2024): 1-14, https://doi.org/10.1080/07391102.2024.2335293.

[31] R. Sharma, Y.-H. Chiang, H.-C. Chen, et al., “Dual Inhibition of CYP17A1 and HDAC6 by Abiraterone-Installed Hydroxamic Acid Overcomes Temozolomide Resistance in Glioblastoma Through Inducing DNA Damage and Oxidative Stress,” Cancer Letters 586 (2024): 216666, https://doi.org/10.1016/j.canlet.2024.216666.

[32] F. De Bacco, E. Casanova, E. Medico, et al., “The MET Oncogene Is a Functional Marker of a Glioblastoma Stem Cell Subtype,” Cancer Research 72 (2012): 4537-4550, https://doi.org/10.1158/0008-5472.CAN-11-3490.

[33] C. A. Gilbert, M. C. Daou, R. P. Moser, and A. H. Ross, “Γ-Secretase Inhibitors Enhance Temozolomide Treatment of Human Gliomas by Inhibiting Neurosphere Repopulation and Xenograft Recurrence,” Cancer Research 70 (2010): 6870-6879, https://doi.org/10.1158/0008-5472.CAN-10-1378.

[34] B. Rangone, B. Ferrari, V. Astesana, et al., “A New Platinum-Based Prodrug Candidate: Its Anticancer Effects in B50 Neuroblastoma Rat Cells,” Life Sciences 210 (2018): 166-176, https://doi.org/10.1016/j.lfs.2018.08.048.

[35] B. Ferrari, E. Roda, E. C. Priori, et al., “A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect With Hadrontherapy: Novel Strategy to Treat Glioblastoma,” Frontiers in Neuroscience 15 (2021): 1-28, https://doi.org/10.3389/fnins.2021.589906.

[36] B. Ferrari, F. Urselli, M. Gilodi, et al., “New Platinum-Based Prodrug Pt(IV)Ac-POA: Antitumour Effects in Rat C6 Glioblastoma Cells,” Neurotoxicity Research 37 (2020): 183-197, https://doi.org/10.1007/s12640-019-00076-0.

[37] L. Gaiaschi, C. Favaron, C. Casali, et al., “Study on the Activation of Cell Death Mechanisms: In Search of New Therapeutic Targets in Glioblastoma Multiforme,” Apoptosis 28 (2023): 1241-1257, https://doi.org/10.1007/s10495-023-01857-x.

[38] L. Gaiaschi, E. Roda, C. Favaron, et al., “The Power of a Novel Combined Anticancer Therapy: Challenge and Opportunity of Micotherapy in the Treatment of Glioblastoma Multiforme,” Biomedicine & Pharmacotherapy 155 (2022): 113729, https://doi.org/10.1016/j.biopha.2022.113729.

[39] D. Bhamidipati, J. I. Haro-Silerio, T. A. Yap, and N. Ngoi, “PARP Inhibitors: Enhancing Efficacy Through Rational Combinations,” British Journal of Cancer 129 (2023): 904-916, https://doi.org/10.1038/s41416-023-02326-7.

[40] F. J. Groelly, M. Fawkes, R. A. Dagg, A. N. Blackford, and M. Tarsounas, “Targeting DNA Damage Response Pathways in Cancer,” Nature Reviews. Cancer 23 (2023): 78-94.

[41] Q. Li, W. Qian, Y. Zhang, L. Hu, S. Chen, and Y. Xia, “A New Wave of Innovations Within the DNA Damage Response,” Signal Transduction and Targeted Therapy 8 (2023): 1-26, https://doi.org/10.1038/s41392-023-01548-8.

[42] A. M. Mendes-Pereira, S. A. Martin, R. Brough, et al., “Synthetic Lethal Targeting of PTEN Mutant Cells With PARP Inhibitors,” EMBO Molecular Medicine 1 (2009): 315-322, https://doi.org/10.1002/emmm.200900041.

[43] B. McEllin, C. V. Camacho, B. Mukherjee, et al., “PTEN Loss Compromises Homologous Recombination Repair in Astrocytes: Implications for Glioblastoma Therapy With Temozolomide or Poly(ADP-Ribose) Polymerase Inhibitors,” Cancer Research 70 (2010): 5457-5464, https://doi.org/10.1158/0008-5472.CAN-09-4295.

[44] Y. Zhou, C. Fang, H. Xu, et al., “Ferroptosis in Glioma Treatment: Current Situation, Prospects and Drug Applications,” Frontiers in Oncology 12 (2022): 1-13, https://doi.org/10.3389/fonc.2022.989896.

[45] X. K. Zhang, S. Y. Xi, K. Sai, et al., “Cytoplasmic Expression of BAP1 as an Independent Prognostic Biomarker for Patients With Gliomas,” International Journal of Clinical and Experimental Pathology 8 (2015): 5035-5043.

[46] S.-A. Lee, D. Lee, M. Kang, et al., “BAP1 Promotes the Repair of UV-Induced DNA Damage via PARP1-Mediated Recruitment to Damage Sites and Control of Activity and Stability,” Cell Death and Differentiation 29 (2022): 2381-2398, https://doi.org/10.1038/s41418-022-01024-w.

[47] J. Kwon, D. Lee, and S.-A. Lee, “BAP1 as a Guardian of Genome Stability: Implications in Human Cancer,” Experimental & Molecular Medicine 55 (2023): 745-754, https://doi.org/10.1038/s12276-023-00979-1.

[48] Y. Ishii, K. K. Kolluri, A. Pennycuick, et al., “BAP1 and YY1 Regulate Expression of Death Receptors in Malignant Pleural Mesothelioma,” Journal of Biological Chemistry 297 (2021): 101223, https://doi.org/10.1016/j.jbc.2021.101223.

[49] M. Carbone, J. W. Harbour, J. Brugarolas, et al., “Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer,” Cancer Discovery 10 (2020): 1103-1120, https://doi.org/10.1158/2159-8290.CD-19-1220.

[50] F. Dai, H. Lee, Y. Zhang, et al., “BAP1 Inhibits the ER Stress Gene Regulatory Network and Modulates Metabolic Stress Response,” Proceedings of the National Academy of Sciences of the United States of America 114 (2017): 3192-3197, https://doi.org/10.1073/pnas.1619588114.

[51] D. Sanges and V. Marigo, “Cross-Talk Between Two Apoptotic Pathways Activated by Endoplasmic Reticulum Stress: Differential Contribution of Caspase-12 and AIF,” Apoptosis 11 (2006): 1629-1641, https://doi.org/10.1007/s10495-006-9006-2.

[52] J. T. Chen, C. Y. Huang, Y. Y. Chiang, et al., “HGF Increases Cisplatin Resistance via Down-Regulation of AIF in Lung Cancer Cells,” American Journal of Respiratory Cell and Molecular Biology 38 (2008): 559-565, https://doi.org/10.1165/rcmb.2007-0001OC.

[53] K. Letkovska, P. Babal, Z. Cierna, et al., “Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors,” Cancers (Basel) 13 (2021): 1-17, https://doi.org/10.3390/cancers13040776.

[54] Z. Wang, C. Yuan, Y. Huang, et al., “Decreased Expression of Apoptosis-Inducing Factor in Renal Cell Carcinoma Is Associated With Poor Prognosis and Reduced Postoperative Survival,” Oncology Letters 18 (2019): 2805-2812, https://doi.org/10.3892/ol.2019.10630.

[55] Z. Xiong, M. Guo, Y. Yu, et al., “Downregulation of AIF by HIF-1 Contributes to Hypoxia-Induced Epithelial-Mesenchymal Transition of Colon Cancer,” Carcinogenesis 37 (2016): 1079-1088, https://doi.org/10.1093/carcin/bgw089.

[56] X. G. Mao, X. Y. Xue, R. Lv, et al., “CEBPD Is a Master Transcriptional Factor for Hypoxia Regulated Proteins in Glioblastoma and Augments Hypoxia Induced Invasion Through Extracellular Matrix-Integrin Mediated EGFR/PI3K Pathway,” Cell Death & Disease 14 (2023): 269, https://doi.org/10.1038/s41419-023-05788-y.

[57] L. Pang, S. Guo, F. Khan, et al., “Hypoxia-Driven Protease Legumain Promotes Immunosuppression in Glioblastoma,” Cell Reports Medicine 4 (2023): 101238, https://doi.org/10.1016/j.xcrm.2023.101238.

[58] Y. Li, D. Zhang, X. Wang, et al., “Hypoxia-Inducible MIR-182 Enhances HIF1α Signaling via Targeting PHD2 and FIH1 in Prostate Cancer,” Scientific Reports 5 (2015): 1-13, https://doi.org/10.1038/srep12495.

[59] Z. Zhang, L. Yao, J. Yang, Z. Wang, and G. Du, “PI3K/Akt and HIF-1 Signaling Pathway in Hypoxia-Ischemia (Review),” Molecular Medicine Reports 18 (2018): 3547-3554, https://doi.org/10.3892/mmr.2018.9375.

[60] W. Zundel, C. Schindler, D. Haas-Kogan, et al., “Loss of PTEN Facilitates HIF-1-Mediated Gene Expression,” Genes & Development 14 (2000): 391-396, https://doi.org/10.1101/gad.14.4.391.

[61] T. Asai, M. Yokota, H. Isomura, et al., “Treatment of PTEN-Null Breast Cancer by a Synthetic Lethal Approach Involving PARP1 Gene Silencing,” Journal of Pharmaceutical Sciences 112 (2023): 1908-1914, https://doi.org/10.1016/j.xphs.2023.02.017.

[62] A. Ertay, R. M. Ewing, and Y. Wang, “Synthetic Lethal Approaches to Target Cancers With Loss of PTEN Function,” Genes & Diseases 10 (2023): 2511-2527, https://doi.org/10.1016/j.gendis.2022.12.015.

[63] J. M. Martí, A. Garcia-Diaz, D. Delgado-Bellido, et al., “Selective Modulation by PARP-1 of HIF-1α-Recruitment to Chromatin During Hypoxia Is Required for Tumor Adaptation to Hypoxic Conditions,” Redox Biology 41 (2021): 101885, https://doi.org/10.1016/j.redox.2021.101885.

[64] P. E. Bunney, A. N. Zink, A. A. Holm, et al., “乳鼠心肌提取 HHS Public Access,” Physiology & Behavior 176 (2017): 139-148, https://doi.org/10.1016/j.leukres.2016.03.007.Histone.

[65] B. C. Valdez, Y. Nieto, B. Yuan, D. Murray, and B. S. Andersson, “HDAC Inhibitors Suppress Protein Poly(ADP-Ribosyl)Ation and DNA Repair Protein Levels and Phosphorylation Status in Hematologic Cancer Cells: Implications for Their Use in Combination With PARP Inhibitors and Chemotherapeutic Drugs,” Oncotarget 13 (2022): 1122-1135, https://doi.org/10.18632/oncotarget.28278.

[66] Q. Hao, H. Lu, and X. Zhou, “A Potential Synthetic Lethal Strategy With PARP Inhibitors: Perspective on Inactivation of the Tumor Suppressor P53 by Long Noncoding RNA RMRP,” Journal of Molecular Cell Biology 13 (2021): 690-692, https://doi.org/10.1093/jmcb/mjab049.

[67] P. Palumbo, F. Lombardi, F. R. Augello, et al., “Biological Effects of Selective COX-2 Inhibitor NS398 on Human Glioblastoma Cell Lines,” Cancer Cell International 20 (2020): 1-17, https://doi.org/10.1186/s12935-020-01250-7.

[68] F. Lombardi, F. R. Augello, S. Artone, et al., “Up-Regulation of Cyclooxygenase-2 (COX-2) Expression by Temozolomide (TMZ) in Human Glioblastoma (GBM) Cell Lines,” International Journal of Molecular Sciences 23, no. 3 (2022): 1545, https://doi.org/10.3390/ijms23031545.

[69] J. K. Loh, S. L. Hwang, A. S. Lieu, T. Y. Huang, and S. L. Howng, “The Alteration of Prostaglandin E2 Levels in Patients With Brain Tumors Before and After Tumor Removal,” Journal of Neuro-Oncology 57 (2002): 147-150, https://doi.org/10.1023/A:1015782809966.

[70] J. Qiu, Z. Shi, and J. Jiang, “Cyclooxygenase-2 in Glioblastoma Multiforme,” Drug Discovery Today 22 (2017): 148-156, https://doi.org/10.1016/j.drudis.2016.09.017.

[71] L. Y. Pang, E. A. Hurst, and D. J. Argyle, “Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells During Therapy,” Stem Cells International 2016 (2016): 2048731, https://doi.org/10.1155/2016/2048731.

[72] Y. Wang, H. Qi, Y. Liu, et al., “The Double-Edged Roles of ROS in Cancer Prevention and Therapy,” Theranostics 11 (2021): 4839-4857, https://doi.org/10.7150/thno.56747.

[73] B. Perillo, M. Di Donato, A. Pezone, et al., “ROS in Cancer Therapy: The Bright Side of the Moon,” Experimental & Molecular Medicine 52 (2020): 192-203, https://doi.org/10.1038/s12276-020-0384-2.

[74] S. Arfin, N. K. Jha, S. K. Jha, et al., “Oxidative Stress in Cancer Cell Metabolism,” Antioxidants 10 (2021): 1-28, https://doi.org/10.3390/antiox10050642.

[75] J. Wei, K. Zhu, Z. Yang, et al., “Hypoxia-Induced Autophagy Is Involved in Radioresistance via HIF1A-Associated Beclin-1 in Glioblastoma Multiforme,” Heliyon 9 (2023): e12820, https://doi.org/10.1016/j.heliyon.2023.e12820.

[76] W. Chen, H. Zhao, and Y. Li, “Mitochondrial Dynamics in Health and Disease: Mechanisms and Potential Targets,” Signal Transduction and Targeted Therapy 8 (2023): 333, https://doi.org/10.1038/s41392-023-01547-9.

[77] H. Xu, C. Hu, Y. Wang, et al., “Glutathione Peroxidase 2 Knockdown Suppresses Gastric Cancer Progression and Metastasis via Regulation of Kynurenine Metabolism,” Oncogene 42 (2023): 1994-2006, https://doi.org/10.1038/s41388-023-02708-4.

[78] X. Liu, D. Li, W. Pi, et al., “LCZ696 Protects Against Doxorubicin-Induced Cardiotoxicity by Inhibiting Ferroptosis via AKT/SIRT3/SOD2 Signaling Pathway Activation,” International Immunopharmacology 113 (2022): 109379, https://doi.org/10.1016/j.intimp.2022.109379.

[79] Y. Zheng, Y. Huang, Y. Xu, L. Sang, X. Liu, and Y. Li, “Ferroptosis, Pyroptosis and Necroptosis in Acute Respiratory Distress Syndrome,” Cell Death Discovery 9 (2023): 1-12, https://doi.org/10.1038/s41420-023-01369-2.

[80] C. H. Chien, J. Y. Chuang, S. T. Yang, et al., “Enrichment of Superoxide Dismutase 2 in Glioblastoma Confers to Acquisition of Temozolomide Resistance That is Associated With Tumor-Initiating Cell Subsets,” Journal of Biomedical Science 26 (2019): 1-16, https://doi.org/10.1186/s12929-019-0565-2.

[81] Z. Wang, Y. Xia, Y. Wang, et al., “The E3 Ligase TRIM26 Suppresses Ferroptosis Through Catalyzing K63-Linked Ubiquitination of GPX4 in Glioma,” Cell Death & Disease 14 (2023): 695, https://doi.org/10.1038/s41419-023-06222-z.

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2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.